Esters of di-substituted acetic acids and sulfur containing tertiary amino alkanols



UNITED STATE Patented June 2t), 1950 ESTERS OF DI-SUBSTITUTED ACETIC ACIDS AND SULFUR CONTAINING TERTIARY AMINO ALKANOLS Raymond 0. Clinton, Albany County, and Wolf- S PATENT OFFICE corporation of Delaware No Drawing. Application July 24, 1948, Serial No. 40,614

9 Claims. (Cl. 260-469) This invention relates to basic esters derived from disubstituted-acetic acids and sulfur-containing tertiary-aminoalkanols, to addition salts thereof, and to methods of preparing said basic is 1 to 2; and B is a lower aliphatic tertiaryamino group.

In the above formula, the groups designated as R and R, which can be the same or difierent, are each radicals of preferably 3-10 carbon atoms. When R and R are either aryl or aralkyl, the radicals can be nuclearly-substituted by groups such as alkoxyl, including methoxyl and ethoxyl, etc., lower alkyl such as methyl and ethyl, etc., halo, amino, alkylamino, dialkylamino, and the like. When R or R are cycloalkyl, such radicals as cyclohexyl, cyclopentyl, Z-methylcyclohexyl, cyclopropyl, and the like are included. In addition, R and R, when aryl, can be linked in ortho positions, either directly to form the fluorene ring or though a bridge involving such elements as carbon, nitrogen, oxygen, and sulfur to form the rings of 9,10-dihydroanthracene, acridan, Xantheme, and thioxanthene, respectively. The lower alkylene radicals, designated by Y and Z, preferably have 2 to 4 carbon atoms, including such groups as --CH2CH2, -CH2CH2CH2, -CH2CH2CH2CH2-, and

The lower aliphatic tertiary-amino group, shown above as .B, comprehends lower dialkylamino groups illustrated by examples such as dimethylamino, diethylamino, ethylmethylamino, di-nbutylamino, and the like; and lower saturated N- heterocyclic groups illustrated by examples such as l-piperidyl, 2-methyl-l-piperidyl, l-pyrrolidyl, 4-morpholinyl, and the like. In other words, BH designates a lower aliphatic secondary-amine as illustrated by diethylamine, di-n-butylamine, 2,6- dimethylpiperidine, and the like.

Specific illustrations of our invention follow: (1) 3 (2 dimethylaminoethylmercapto) 2- propyl diphenylacetate,

oomnofloooononrsqvmommonm esters. 5

We have found that basic compounds having the following formula exhibit useful pharmaco- (2) 3 (3 (1 piperidyl) propylmercapto) 2- logical properties; propyl fluorene-Q-carboxylate,

CHOOO-(Y-S),.Z-B Olin-0E R1 HCOOCHCHz-S-CHaCHzCHgM CH: where R and R are aryl, aralkyl, or cycloalkyl H; CHgOfi radicals; Y and Z are lower alkylene radicals; n m

(3) 2 (2 diethylaminoethylmercapto) ethyl 9,10-dihydro-9-anthroate,

Ha HO O O CHaCHr-S-CHzOH:N(UzH5)g (4:) 3 (2 (2 methyl-l-piperidyl)ethylmercapto) -2-propy1 cyclohexylphenylacetate,

GeHa GET-CH2 oHooooHom-s-omom om can H. era-oh,

(5) 2 (3 diethylaminopropylmercapto) ethyl dibenzylacetate,

In practicing our invention we prepared our basic esters by one of two general methods: (a) reaction of a di-substituted-acetyl halide of the formula R(R)CHCO-ha1ogen with the appropriate basic alcohol of the formula,

may produce mixtures from which no crystalline;

substance can be obtained. In many instances the reaction between the acid halide and the al-*" cohol may result in the deposition ofthe hydro chloride in a form which resists crystallization, or which if crystallized is found-to be hygroscopic.

solubility of these hydrochlorides is often advantageous. Where solid crystalline salts of .convenient physical properties are desired, we have found the citrates to be suitable. These are prepared by treating a solution of the free basic" ester with an equivalent of citric acid monohydrate.

Preparation of the intermediate sulfur-containing tertiary-aminoalkanols are described in the literature by Clinton -et-al., J. Am. Chem. Soc. 67, 594 (1945) and ibid..69, 519 (1947).

We found it convenient to. isolate and use the basic esters of our invention as the water soluble citric acid salts or hydrochloric acid addition salts. water-soluble salts, such as those derived from other non-toxic organic acids, including tartaric acid, succinic acid, and the like, and other nontoxic inorganic acids, including hydro-bromic acid, sulfuric acid, phosphoric acid, and the like, have equivalent therapeutic efficacy andare within the scope of our invention.

Also comprehended by our invention are the quaternary salts of our basic esters, said salts being derived from esters of strong inorganic acids and organic sulfonic acids, and such esters including methyl bromide, ethyl sulfate, n-propyl iodide, benzyl chloride, methyl para-toluenesulfonate, and the like.

The following examples illustrate specific .embodiments of the invention.

Example 1 2 (2 diethylaminoethylmcrcapto)cthyl dz"- phem/Zacetate hydrochZorzde.-To an ice-cooled solution of benzene containing 13.0 g. (0.0565 mole) of diphenylacetyl chloride and 100 ml. of dry benzene is added during a live minute period with shaking a cold solution of 10.0 g, {0.0.565 mole) of 2-(2-diethylaminoethylmercapto)ethanol in 50 m1. of dry benzene. The clear solution is warmed for fifteen minutes on the steam bath and then cooled. After-addition of about 500 ml. of petroleum ether ,(n-.pentan e.-fraction),, there separates an oil which crystallizes on 0.01.- ing and triturating. Three recrystallizations of this material from .ethyl acetate results in 15.8 g. of large white prisms, M. P. 94-5 C. This productis 2 (2 diethylaminoethylmercapto)ethyl diphenylacetate hydrochloride.

When the above procedure is used, but substituting 3 (2 (2-methyl-l-piperidyl).ethylmercapto)-2- propanol for 2-(2-diethylaminoethylmercaptoiethanol, there is formed, as the final product, .3 .(2-fz-methyl-l-piperidyl)ethy mercapto) -.2-propy1 ,dipbenylacetate hydrochloride.

Example 2 3- (2 diethylaminoethylmercapto)propyl dzphenylucetate citrate-The condensation of 3- (2-diethylaminoethylmercapto)propanol and diphenylacetyl chloride is carried out as described in Example 1. The crude crystalline hydrochloride (M. P. ca. 21 C.) is converted to the free base with ammonia and the free base extracted with ethyl acetate. The dried ethyl acetate solution of the base is treated with a slight excess of citric acid monohydrate in absolute ethanol solution. The resulting citrate is recrystallized from :a'bsolute ethanol-ethyl acetate to give an 87% However the sometimes inconvenient physical properties of these hydrochlorides in the 7 solid state do not preclude their effective preparation and use in solution, and in fact the high yield of 3-(2-diethylaminoethylmercapto) propyl diphenylacetate citrate, M. P. 1l2'.5-3.0 C.

Other esters of diphenylacetic acid can be .prepared according to the above procedure if, in place of 3-(Z-diethylaminoethylmercapto)pro- .panol, othercorresponding basic sulfur-containing alcohols are utilized. Thus, by using as the 'basic alcohols, 3-(2-dimethylaminoethylmercapto)-2-propanol and Z-(Z-dimethylaminoethylmercapto) ethanol, and, further, by substituting It is, of course, understood that other E about two and one-half hours.

dry ether for benzene as the reaction solvent, there is obtained, respectively, 3-(2-dimethylaminoethylmercapto)- 2- propyl diphenylacetate citrate, M. P. 6540? C. (recrystallized from acetone) and 2- (2-dimethylaminoethylmercapto) ethyl diphenylacetate citrate, M. P. 73-5 C. .(re crystallized from acetone. v

Further, there also can .beprepared basic esters of the above type, but containing more than one sulfur atom in the alcohol portion of the esters. For example, if the above procedure is carried out, but using as the basic alcohol 2-(2-(2- diethylaminoethylmercapto) etlhylmercapto) ethanol, the resulting product is 2-(2-(2-diethyb aminoethylmercapto)ethylmercapto) e t h yl difphenylacetate citrate, a waxy white crystalline Example 3 2 ('2 diethylaminoethylmercapto)ethyl dzbenzylacetate citrat'e.-A mixture 0f-10 g. (0.042 mole) of dibenzylacetic acid, 30 ml. of thionyl chloride, and fiofml; of chloroform is refluxed for The excess solvent and thionyl chloride are removed as completely as possible by in 'vacuo distillation using a water pump and a hot-water bath. The residual dibenzylacetyl chloride isydissolved in 25' m1. of dry benzene; the solution is cooled in 'ice water; and asolution of' 7.4 g. (-0.042 mole) of -2-'('2-di-' ethylaminoethylmercapt'o)ethanol in 25 ml. of dry benzene is slowly added with shaking. After the "resulting mixture-has been allowed to warm up to room temperature and stand at that temperaturefor about two hours, it is then refluxed on the water bath for twenty minutes. The cooled benzene solutionis washed several times with cold 40% potassium carbonate solution and dried over anhydrous sodium sulfate. The resi- .dualcil after removing the benzene am unts t 1.62 a; this isdissolved sin v.25 :ml. -.of dry acetone. and the solution .is treated with a solutiQn of 8.4 a. of citric acid monohydrate in abou .35 m1. of dry. acetone. The whi e. v lumi ou precipitate is filtered and recrysta11ized from ac one to yield 17.4 g. (7.1%) of .2-f2 diethylaminoethylm rcaptoi-ethyl dibenzylacetate citrate, P. --v 101" C. e If the above pr cedure followed. but usin :18 ether as the reactionsclvent in p ace o 'benzenc encerof a small amount of sodium in petroleum ether (fraction of mixed octanes), 'adding'an equal volume of benzene, washing'the mixture with water, drying the same over anhydrous sodium-sulfate, removing the solvents, and treatihg" the residual oil" as described in Example 3 above. This'preparation also can be carried out .by using sodium ethoxide as the basic catalyst in place ofsodium or by'using no basic catalyst.

Example 4 3 (2 -dimethylaminoeihylmercapto) propyl fluorene 9'- carboxylate -citrate.-Fluorene-9-carboxylic acid is esterified with methanol by bubbling hydrogen chloride through a solution of the acid in methanol. The resulting methyl fluorene-Q-carboxylate distills at 223-6 C. at 40 mm. and melts at 63 C.

A mixture of g. (0.02 mole) of methyl fluorene-Q-carboxylate 4.3 g. (0.026 mole) of 3-(2- dimethylaminoethylmer'capto)propanol, and 0.1 g. (0.005 mole) of sodium metal in 200 ml. of petroleum ether (fraction of mixed octanes) is refluxed for three hours. Nearly all of the petroleum ether is then removed by distilling in vacuo to yield a clear amber liquid residue which is dissolved in 100 ml. of ether. The ether solution is washed several times with water and dried over anhydrous sodium sulfate. Removal of the ether by distilling in vacuo leaves 6.4 g. of the basic ester, which is treated in acetone solution with an equivalent amount (3.6 g.) of citric acid monohydrate. The precipitated salt is collected and recrystallized from acetone-petroleum ether (n-hexane fraction) to give 7.1 g. (61%) of white needles, M. P. 78-80 C. (with efiervescence) this product is 3-(2-dimethylaminoethylmercapto)- propyl fluorene-Q-carboxylate citrate.

Using the above procedure but different basic sulfur-containing alcohols the following compounds are obtained: 3-(3-(1-piperidyDpropylmercapto)-2-propyl fluorene-Q-carboxylate citrate, which, on melting, bubbles from 71 0.; and 2- (2-diethylaminoethylmercapto) ethyl fluorene- Q-carboxylate citrate, M. P. 95-7 C. (with effervescence).

Example 5 2 (2 diethylaminoethylmercapto) ethyl 9,10- dihydroanthracene 9 carboxylate hydrochloride.A mixture of 6.55 g. (0.029 mole) of 9,10 dihydroanthracene-9-carboxylic acid (prepared using n-butyl lithium as described by Burtner and Cusic, J. Am. Chem. Soc., 65, 1582 (1943)), 12 ml. of purified thionyl chloride, and 15 ml. of dry chloroform is refluxed for three hours. The excess thionyl chloride and solvent are removed by distilling in vacuo. The residual 9,10- dihydroanthracene-9-carboxylic acid chloride is dissolved in 30 ml. of dry ether, and to this solution, while being cooled, is slowly added a solution of 5.2 g. (0.0294 mole) of 2-(2-diethylaminoethylmer'captomthanol 11 30 ml; of dry ether. The resulting mixture-is allowed-to stand at room temperature afew minutesand then placed in the refrigerator overnight. The I supernatant liquid-fist decanted from the-precipitated mixture or 'sol-id"and"gum. On-triturating this-mixture with cold, dryacetone, thegum dissolvesleaving a white solidfiwhich is collected and-recrystallized from acetone to yield 3.6g. (33%) of -2'--(2- diethylaminoethylmercapto) ethyl 9,10 dihydroanthracene-S-carboxylate hydrochloride, M. P. 137-15, c.

Eatample 6 3- (2-diethylaminoethylmercapto) propyl cyclohezcylphenylacetate citrate.-After.- a mixture of 10 g. of, cyclohexylphenylacetic acid and 10 nl. of thionyl chloride has been refluxed forthree hours on a steam bath, the excej ssthionyli. chlo% ride is removed by distillation, ,and the residue is distilled invacuo, yielding 9.57 g. (08%) of cyclohexylphenylacetyl chloride, B. P. 10%-7; at 0.1mm. To the 9.57 g. of acid chloride. is added, with external cooling inice water, 7.7 g. of 3 7 (2 diethylaminoethylmercapto) propanol, whereupon there results, after evolution of, heat, a s i dm A ter. a d gv rn ht i the refrigerator, the mass is broken up and dissolved in water (about 150 ml.), and the resulting solution is filtered. The filtrate is'made alkaline with a 10% aqueous sodium carbonate solution; the resulting alkaline solution is extracted with ether; and the ethereal extract is dried with anhydrous sodium sulfate. After removal of the ether by distillation, the residual oil is dissolved in about 25 ml. of dry acetone and there is added a solution of 8.5 g. of citric acid monohydrate in about 50 ml. of dry acetone. The resuIting solution is placed in a refrigerator for several days. The white crystals that separate are filtered, washed with cold, dry acetone, and recrystallized twice from acetone, yielding 17.2 g. of 3 -(2 diethylaminoethylmercapto) propyl cyclohexylphenylacetate citrate, M. P. -9 C. (with eifervescence) Similarly, there can be prepared other basic esters of cyclo-hexylphenylacetic acid by following the above directions but using other sulfurcontaining basic alkanols. Such esters are 3-(2- diethylaminoethylmercapto) 2 propyl cyclohexylphenylacetate citrate, M. P. -4 C. (with effervescence) and 2-(Z-diethylaminoethylmercapto) ethyl cyclohexylphenylacetate citrate, M. P.

102-6 (with effervescence).

We claim:

1. A compound selected from the group consisting of a basic compound having the formula \CHCOO-(Y-S),,Z-B R! where R and R. are members of the group consisting of aryl, aralkyl, and cycloalkyl radicals; Y and Z are lower alkylene radicals; n is 1 to 2; and. B is a lower aliphatic tertiary-amino group, and addition salts thereof.

2. A compound selected from the group consisting of a basic ester having the formula where Y and Z are lower alkylene radicals, and B is a lower aliphatic tertiary-amino group, and

[5 addition salts thereof.

CHPCH, )CHOOO-Y-B-Z-BH Ce. 1 a! .oHr'-:0

where Yand z are lower alkylene radicals vand B is a. lower aliphatic tertiary-amino group, and addition salts thereof.

5. A compound selected from the group consisting of 2-(2-diethylaminoethylmercapto) ethyl diphenylacetate and addition *salts thereof.

6. A compound selected from the group consisting of 2- (2-diethylaminoethylmereapto) ethyl dihenzylacetate and addition salts thereof.

7. A compound selected from the group eonsisting of 2-(z-diethylaminoethylmercapto) ethyl vs:yelche o l rimy a. ate" and addition sa s there of.

5 ethyl diphenylacetateend addition salts-thereof.

9. A compound. selected from the group consistingpf 3- (2 diethylaminoethylmeroapto)pgaopyl diphenylacetete and addition salts thereof. RAYMOND O. CLINTON, v, 1WOL GANGHUBER. 1 vCI L RGE M. EOHI E v -,C. LA KQWSKI- REFERENCES CITED J6 The following references-are-of :recordain file :of this patent: Y

"UNITED STATES PATENTS Nome. Mi che t a May OTHER REFERENCES Gilman etial; J ourn; PharmLandeExp. Then." March 1942, pages 290-307.

Clinton et aL: J. :Am. Chem. Soc., vol. 67, page 594 (1945). i 7

Clinton etala ipid, vol 59,.page5l97t194'7).

Numb

ate 2,079,962 ll, 193T 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A BASIC COMPOUND HAVING THE FORMULA 